POS0400 MODULATION OF HUMAN EARLY B CELL DEVELOPMENT THROUGH TARGETED DEGRADATION OF IKAROS AND AIOLOS WITH IBERDOMIDE
Authors: I. Janowska, J. Korzhenevich, J. Staniek, R. Lorenzetti, L. Konstantinidis, M. Erlacher, P. Schafer, R. Voll, J. Thiel, N. Venhoff, M. Rizzi
Journal: Annals of the Rheumatic Diseases (2022)

Background B differentiation in the bone marrow (BM) is impaired in patients carrying mutation in the IKFZ1 gene, coding for Ikaros a zinc-finger transcription factor. High Ikaros expression is on the contrary associated with systemic lupus erythematosus[1] and multiple myeloma[2]. Targeted treatment with iberdomide, a cereblon modulator which enhances degradation of Ikaros and Aiolos, is under clinical investigation in multiple myeloma patients and systemic lupus erythematosus. However, consequences of the treatment on human early B cell development remain elusive. Immature B cells develop in the BM from hematopoietic stem cells. An intricate network of transcription factors regulates the maturation process. Ikaros and Aiolos regulate gene expression during B cell development. As reported in mice, Ikaros is essential for the commitment to the lymphoid lineage and later, together with Aiolos, ensures the transition from pre-BII large to pre-BII small cells. Objectives Investigate the effect of iberdomide (CC-220) on human early B cell development simulated in vitro. Methods We tested the impact of iberdomide on short term culture of BM-derived lymphocytes and in a unique in vitro modeling of early B cell development starting from cord blood (CB)- CD34+ progenitors [3, 4]. We used multi-dimensional spectra flow cytometry (17-color pan-el) to dissect early B cell subpopulations. Results Iberdomide treatment led to enhanced degradation of Ikaros and Aiolos in both BM- and CB-derived cultures. Addition of iberdomide early (day 7) to the CB-derived culture impaired the specification to the lymphoid lineage and later also the commitment to the B cell lineage. These observations were confirmed by reduced E2A and PAX5 gene expression, respectively. Treatment with iberdomide on B cell precursors (pro- and pre-B cells, day 28 of culture) on one side it enhanced the proliferation of early progenitors resulting in increased amount of CD10+CD38+ lymphoid-committed cells. On the other side, it resulted in a accumulation of pre-B cells and inefficient development of immature B cells. Conclusion Iberdomide impairs the commitment to the lymphoid lineage by enhancing Ikaros’ degrada-tion. When targeting already committed B cells, iberdomide treatment undermines the transition of pre-BII large to pre-BII small cells due to increased Aiolos’ degradation, conse-quently impairing the development of immature B cells. Our data can instruct immunologi-cal monitoring of patients treated with iberdomide, and provide insights in the mechanisms of therapeutic efficacy. References [1]Rivellese, F., et al., Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus. Lupus Sci Med, 2021. 8(1). [2]Thakurta, A., et al., Developing next generation immunomodulatory drugs and their combinations in multiple myeloma. Oncotarget, 2021. 12(15): p. 1555-1563. [3]Kraus, H., et al., A Feeder-Free Differentiation System Identifies Autonomously Proliferating B Cell Precursors in Human Bone Marrow. The Journal of Immunology, 2014. 192(3): p. 1044-1054. [4]Troilo, A., et al., Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency. Blood, 2020. 135(17): p. 1452-1457. Disclosure of Interests Iga Janowska: None declared, Jakov Korzhenevich: None declared, Julian Staniek: None declared, Raquel Lorenzetti: None declared, Lukas Konstantinidis: None declared, Miriam Erlacher: None declared, Peter Schafer Employee of: BMS, Reinhard Voll: None declared, Jens Thiel Grant/research support from: BMS (former Cellgene), Nils Venhoff: None declared, Marta Rizzi Grant/research support from: BMS (former Cellgene)